Recent advances in the renal-skeletal-gut axis that controls phosphate homeostasis

Under physiological conditions, homeostasis of inorganic phosphate (Pi) is tightly controlled by a network of increasingly more complex interactions and direct or indirect feedback loops among classical players, such as vitamin D (1,25(OH)2D3), parathyroid hormone (PTH), intestinal and renal phosphate transporters, and the recently described phosphatonins and minhibins. A series of checks and balances offsets the effects of 1,25(OH)2D3 and PTH to enable fine-tuning of intestinal and renal Pi absorptive capacity and bone resorption and mineralization. The latter include PHEX, FGF-23, MEPE, DMP1, and secreted FRP4. Despite this large number of regulatory components with complex interactions, the system has limited redundancy and is prone to dysregulation under pathophysiological conditions. This article reviews and synthesizes recent advances to present a new model of Pi homeostasis.